A novel Triadin variant causes a severe clinical CPVT phenotype in two young brothers

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Dokumenter

ABSTRACT - Cardiostim Vienna 2017 (18th June – 21th June) Title: A novel Triadin variant causes a severe clinical CPVT phenotype in two young brothers Authors: AK Broendberg1, C Dait2, J Bjerre3, LN Pedersen4, JC Nielsen1 , TJ Corydon2, & HK Jensen1 1Department of Cardiology, Aarhus University Hospital, Denmark 2Department of Biomedicine, Aarhus University, Denmark 3Department of Pediatrics, Aarhus University Hospital, Denmark 4Department of Molecular Medicine (MOMA), Aarhus University Hospital, Denmark Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited cardiac disorder, which enhances susceptibility to ventricular fibrillation (VF) due to altered intracellular calcium handling. The predominant gene in this disease is Ryanodine receptor-2 (RYR2), which is inherited in a dominant fashion. Mutations in Triadin (TRDN) is an extremely rare cause of CPVT and is inherited in a recessive manner. Purpose: To clinically characterize a family with a novel TRDN variant (NM_001251987)c.179T>C (p.Trp60Leu) and to establish functional properties of this variant. Methods: Genomic DNA purified from blood was used for genetic screening in our targeted next generation sequencing gene panel. TRDN wildtype and variant cDNA has been cloned in a pcDNA3.1 expression vector. Following transient transfection of human cells functional properties of Triadin wildtype and variant proteins have been obtained by means of Western blot analysis and immunostaining. Results: Two brothers both collapsed with exercise induced cardiac arrest and VF at the ages of three and two years, respectively. Both were treated with implantable cardioverter-defibrillator (ICD). The oldest brother has received appropriate shock therapy 6 times during exercise or emotional stress within 44 months of observation. He is currently stable on the combination of beta-blocker and flecainide. The youngest brother has not received any ICD therapy within 15 months on beta-blocker therapy. Genetic screening has revealed that both children are homozygote for the TRDN variant (p.Trp60Leu), which was found in heterozygous form in both parents, who are clinically unaffected. Preliminary functional studies have revealed reduced cellular expression of the variant form compared to wildtype. We still need to establish whether the observed findings are due to reduced expression of the TRDN gene and/or enhanced degradation of the corresponding variant protein. Conclusion: We found a novel TRDN variant, causing a severe clinical CPVT phenotype in two very young children. Preliminary functional studies have revealed reduced cellular expression of the variant form compared to wild type.
OriginalsprogEngelsk
Udgivelsesår2019
StatusUdgivet - 2019
BegivenhedEHRA Europace - Cardiostim 2017 - Messe Wien, Wien, Østrig
Varighed: 18 jun. 201721 jun. 2017

Konference

KonferenceEHRA Europace - Cardiostim 2017
LokationMesse Wien
LandØstrig
ByWien
Periode18/06/201721/06/2017

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